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Abstract: SA-PO222

Nephroprotective Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Bak, Stine Thorhauge, Gubra, Hoersholm, Denmark
  • Dalbøge, Louise, Gubra, Hoersholm, Denmark
  • Christensen, Michael, Gubra, Hoersholm, Denmark
  • Secher, Thomas, Gubra, Hoersholm, Denmark
  • Endlich, Nicole, NIPOKA GmbH, Greifswald, Germany
  • Drenic, Vedran, NIPOKA GmbH, Greifswald, Germany
  • Madsen, Martin Roenn, Gubra, Hoersholm, Denmark
  • Hansen, Henrik H., Gubra, Hoersholm, Denmark
  • Rune, Ida, Gubra, Hoersholm, Denmark
  • Fink, Lisbeth N., Gubra, Hoersholm, Denmark
  • Østergaard, Mette Viberg, Gubra, Hoersholm, Denmark
Background

Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female db/db mice.

Methods

Seven weeks after ReninAAV administration and six weeks post-UNx, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included blood pressure, plasma/urine biochemistry, kidney histopathology and RNA sequencing.

Results

Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, podocyte filtration slit density, urine/renal kidney injury molecule-1 (KIM-1) levels and gene expression markers of inflammation and fibrogenesis. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis.

Conclusion

Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Renal outcomes were further improved by combined antihypertensive standard-of-care.